MOTIVATION LETTER Genetic and Molecular Basis of Neurodevelopmental Disorders

Neurodevelopmental disorders are disabilities in the functioning of

the brain that affect a child’s behavior, memory or ability to learn e.g. mental

retardation, dyslexia, attention deficit hyperactivity disorder (ADHD),

learning deficits and autism [1,2].

FIG -1: Depicting normal embryological development. Red indicates sensitive stages

in development and yellow indicates stages that are less sensitive to teratogens[3].

Neurodevelopment begins in the early prenatal stage with a complex

neurological development that begins with proliferation of radial glia and

neurons. These continue to develop in the postnatal years. This process is

not complete until almost 3 years of age.

Migration of neurons, which occurs from the 2nd to the 6th month of

gestation, and again within the cerebellum postnatally, is a very important

and complex process. Synapse formation, which occurs essentially in the

last trimester as well as in the first 2 years of life, is critical to ongoing

functioning and development. Myelination is an important process that

begins in the second half of gestation and goes on to adolescence, with

different systems myelinating at different times, as shown in figure-2

Figure -2 depicting neuronal development at various stages [4].

Figure 3: The determinants of Neurodevelopmental process is

depending multiple factors [5].

Neurodevelopmental behavioral disorders occur most commonly in

industrialized countries. Nearly15% of children is described as having

learning disabilities, developmental delay, attention deficit hyperactivity

disorder, autism, reduced intelligence quotient and cerebral palsy.

Major subclasses of neurodevelopmental disorders:

Intellectual disability Learning disabilities

Communication disorders

Autism spectrum disorders

Neurobehavioral disorders

Neurogenetic disorders Neurometabolic disorders

Neuromuscular disorders Cerebral palsy

Other neuromotor disorders Sensory impairments

Disabilities associated with chronic diseases Traumatic brain injuries

Spinal cord injuries

The majority of children with neurodevelopmental disorders are delayed in

language milestones and many are later diagnosed with language

impairments.

Genetics play an important role in many neurodevelopmental

disorders. However, most neurodevelopmental disorders are multifactorial

in nature. These disorders likely result from a combination of genetic,

biological, psychosocial and environmental risk factors. A broad range of

environmental risk factors may affect neurodevelopment, which are

maternal use of alcohol, tobacco, or teratogenic drugs during pregnancy,

lower socioeconomic status, preterm birth, low birth weight and prenatal or

childhood exposure to certain environmental contaminants.

Lead, methylmercury, and PCBs are widespread environmental

contaminants associated with adverse effects on a child’s developing brain

and nervous system in multiple studies. The National Toxicology Program

(NTP) has concluded that childhood lead exposure is associated with

reduced cognitive function, including lower intelligence quotient (IQ) and

reduced academic achievement. The NTP has also concluded that childhood

lead exposure is associated with attention-related behavioral problems

(including inattention, hyperactivity, and diagnosed attention-

deficit/hyperactivity disorder) and increased incidence of problem

behaviors (including delinquent, criminal, or antisocial behavior).

Figure 4: depicting various environmental factors disturbing the

development of normal neurodevelopmental process [6].

Autism Spectrum Disorders:

Autism spectrum disorders (ASDs) are a group of developmental disabilities

characterized by significant deficits in social, communication, and

behavioral domains. Autistic disorder, Asperger syndrome, and pervasive

developmental disorder are the three ASDs. Persons who have autistic

disorder have significant language delays, social and communication

challenges, and unusual behaviors and interests Research on the genetic

contributions to complex disorders remained minimal until recent years.

The understanding of these neurobehavioral disorders has undergone a

remarkable shift in the past decade, with a surge of research exploring the

genetic basis of these traits and conditions. Momentous discoveries were

first made in heritability estimates and have progressed to the identification

of specific genetic linkages associated with language impairments across a

number of neurodevelopmental disorders.

The initial question of interest was to what degree language

impairment or ASD was due to environmental versus genetic factors. Twin

studies provided our first insights into understanding question, through the

comparison of concordance rates across monozygotic (MZ) and dizygotic

(DZ) twins. Several studies indicated that concordance rates for MZ twins

exceeded those for DZ twins across both Specific language impairment (SLI)

and ASD populations.

In SLI, concordance was found in 70–96% of MZ and 48–69% of DZ

twins. In studies of ASD, the most recent MZ concordance rates hover

between 50 and 77%, while DZ twins showed around 25– 36%

concordance.

From these studies, researchers concluded that both these conditions

are highly heritable, pointing to the role of genetic variation in

neurodevelopmental disorders characterized by language and

communication impairments. A study by Fisher et al., 1998, discovered that

FOXP2, a gene associated with severe speech impairment, on chromosome

7q31, created ripples through the genetic research community, which led to

more research on genetic basis of neurodevelopmental disorders [7]

Approximately 30% of children with epilepsy have autism and/or

intellectual or developmental disabilities. Epileptogenesis is a process that

proceeds over months to years in humans. After an initial precipitating

event such as a prolonged febrile seizure or head trauma, there are

processes that occur very rapidly including ion channel activation,

posttranslational changes, and immediate early genes.

Next, over a period of days to weeks, there are transcriptional events,

neuronal death, and inflammation. Sprouting, network reorganization,

neurogenesis, and gliosis occur over the ensuing weeks, months, and years.

These processes may lead to the development of the first spontaneous seizures,

and then be recapitulated with each seizure, resulting in perpetuation or

progression of epilepsy.

Table 5- some of the genes implicated in the epilepsy [8].

Table-6: The various routes to an epilepsy phenotype can result from gene

defects affecting multiple levels of neuronal function [9].

Table 7: Steps in finding and understanding a novel epilepsy gene which can b targeted for anti epileptic treatment.[9]

CONCLUSION:

We have made great progress since last decade in targeting human

epilepsy genes that has been phenomenal. Many gene defects and

mechanisms can result in a single phenotype, whereas many differing

phenotypes may result from a single gene defect. Some gene defects alter

specific physiologic mechanisms involved in seizure production, such as

ionic-channel function or neurotransmission. Few Other gene defects

produce more diffuse alteration of neuronal function, such as abnormal

development of neuronal structure or synaptic connectivity, altered intra-

cellular signaling, failure of cytoprotective systems, mechanisms, or

disrupted cellular metabolism which resultant in neuronal degeneration.

Development of constructs for region-specific gene expression linking

genotype to the phenotype and at the same time clinically refining the spectrum

of the epilepsies will provide a neurobiologic basis and mechanistic

understanding of the human epilepsies. The challenge to clinicians and

neurobiologists is to unravel this tangled web and translate these advances into

practical applications for early diagnosis, genetic counseling, and innovative

therapies for persons with epilepsy.

References:

.1The diagnostic and statistical manual of mental disorders. 5th ed.

Washington, DC: The American Psychiatric Association; 2013.

2. Kliegman RM, Stanton B, St Geme J, Schor N, Behrman RE. Nelson

textbook of pediatrics. 19th ed. Philadelphia: Saunders Elsevier; 2011.

3.Reprinted from Moore. The developing human. Elsevier Inc., 1973.

4.Rice D, Barone Jr S. Critical periods of vulnerability for the developing

nervous system: evidence from humans and animal models. Environmental

Health Perspectives, 2000, 108(S3):511-533.

5. Grandjean P, Landrigan PJ. Developmental neurotoxicity of industrial

chemicals. Lancet, 2006, 368(9553):2167- 2178.

6. Rice D, Barone Jr S. Critical periods of vulnerability for the developing

nervous system: evidence from humans and animal models. Environ Health

Perspectives, 2000, 108(S3):511-533.

7.Pears KC, Fisher PA 2005 Emotion understanding and theory of mind

among maltreated children in foster care: evidence of deficits. Dev

Psychopathol 17:47– 65.

8. Ortrud K. Steinlein GENETIC MECHANISMS THAT UNDERLIE EPILEPSY

NEUROSCIENCE, VOLUME 5 | MAY 2004,400-408.

9. Asuri N. Prasad, Progress in Epilepsy Research;Recent Advances in the

Genetics of Epilepsy: Insights from Human and Animal Studies, epilepsia 40(

lO):I329-1352. 1999.